Accelerating Transdisciplinary Epidemiology of Colorectal Cancer Summary Tumor evolution is a heterogeneous process influenced by somatic molecular alterations, host immunity, diet, lifestyle, microbiota, and environment. Thus, I plan to take a transdisciplinary approach integrating molecular- level research, population-level study design, and assessment of environment, diet and lifestyle, utilizing my unique interdisciplinary expertise. I have been developing the transdisciplinary field of Molecular Pathological Epidemiology (MPE) with integrated strengths of both pathology and epidemiology. I will pursue two interconnecting synergistic Themes: (1) MPE of colorectal cancer (CRC) and (2) accelerating transdisciplinary epidemiology. In Theme 1, I will integrate tumor molecular and immunity analyses in 2,500 CRCs in the Nurses' Health Study (NHS), the NHS2 and the Health Professionals Follow-up Study (HPFS). I have successfully built an unprecedented high-dimensional CRC database on long-term exposures, tumor pathology, microbial, molecular and immunity data, and clinical outcome, to test the following broad-term hypotheses: (1.1) Dietary, lifestyle, environmental and genetic factors influence CRC incidence differentially by molecular, microbial and immunity subtypes. (1.2) CRC molecular features influence immune response to CRC. (1.3) CRC molecular and immunity status influences patient survival and response to drugs or modifiable dietary, lifestyle or environmental factors. (1.4) The degree of CRC intratumor heterogeneity is associated with worse prognosis and specific epidemiologic, clinical, and pathological features. We will extend our integrative research to various other settings to replicate findings and assess potential effect modifications by ethnic, socioeconomic and other factors. This project may identify potential strategies to target molecular alterations, immunity and microbiota for CRC prevention and therapy. My Theme 2 plans are; (2.1) to develop research frameworks, analysis designs and statistical methods, to address molecular and etiologic heterogeneity of cancer; (2.2) to grow the ongoing International MPE Meeting Series, to facilitate seamless transdisciplinary integration with a goal of making the STROBE-MPE guidelines; and (2.3) to synergize with experts and build new integrative transdisciplinary models, causal inference-MPE and MPE-health communication research. Thus, I aim to promote transdisciplinary integration of molecular pathology and population cancer science, and to address a critical unmet need to integrate analyses of cancer immunity, tumor molecular profiles (including microbiota and intratumor heterogeneity), modifiable exposures, genetics, and CRC incidence and death. I also try to address challenges in transdisciplinary epidemiology, including paucity of interdisciplinary experts and training programs, as well as lack of research guidelines in MPE. My unique qualifications and transdisciplinary research program can not only provide new insights on CRC etiologies in a population-based scale, but also develop novel methods / frameworks, and frontiers of population cancer science. As such, my proposed research will likely have major impacts on future research, clinical practice and public health.